Method of inhibiting sleep apnea

ABSTRACT

A method of inhibiting sleep apnea is disclosed comprising administering an effective amount of 6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidine-L-prolinamide or a pharmaceutically acceptable acid addition salt thereof.

This case is a 371 of PCT/U.S. Pat. No. 96/17,184 filed Oct. 24, 1996.

BACKGROUND OF THE INVENTION

Obstructive sleep apnea is a serious disorder in which normal breathingduring sleep is interrupted for periods of 10 seconds to a minute oreven longer as a result of obstruction of the upper airway. Sleep apneasyndrome also involves decreases in blood oxygen levels. To resumebreathing and restore blood oxygen, the subject must wake up. Thus,normal sleep is interrupted. Sleep apnea may be classified as mild, fiveto 25 events per hour; moderate, 25 to 40 events per hour; or severemore than 40 events per hour. Persons with sleep apnea are preventedfrom attaining essential rest and suffer from chronic sleepfragmentation/deprivation occurring as a consequence of frequent nightlyarousals brought about by critical decreases in blood oxygen levelssecondary to disruptions in respiration. It has been estimated that from1 to 3 percent of the adult population of North America suffers fromsleep apnea. Sleep apnea has been associated with increased risk ofheart attacks or strokes. Sleep apnea sufferers also frequentlyexperience excessive daytime sleepiness which can result in themsuddenly falling asleep while engaged in activities requiring alertness,such as driving a car.

Although consideration has been given to the possibility of treatingsleep apnea with drugs such as medroxyprogesterone, protriptyline,acetazolamide, nicotine or even strychnine, there is currently nosatisfactory pharmacotherapy for sleep apnea. Instead, sleep apnea iscommonly treated either by throat surgery designed to maintain airwaypatency during sleep or with mechanical devices such as dentalretainers. Surgery to remove tissues thought to contribute toobstruction of the airway is effective in only about 50 to 60% ofpatients. Cases of obstructive sleep apnea are generally managed withapparatus known as a continuous positive airway pressure (CPAP) machine.The CPAP comprises a mask that fits over the nose of the patient. Themask has an hose attached to it and a small box with a fan that blowsair through the hose and into the nasal passages. The CPAP machineprovides positive air pressure in the patient airway in order to preventcollapse of the airway which initiates a sleep apnea episode. While theCPAP is generally effective if used consistently, it is also expensive,cumbersome and highly inconvenient, thereby giving rise to significantpatient compliance problems.

Thus, there has remained a substantial need for improved methods oftreating obstructive sleep apnea, and particularly for an effectivepharmacotherapy for treating this disorder.

SUMMARY OF THE INVENTION

Accordingly, it is the object of the present invention to provide amethod of treating patients suffering from obstructive sleep apnea.

A further object of the invention is to provide an effectivepharmacotherapeutical treatment method for obstructive sleep apnea.

Yet another object of the invention is to provide an effective treatmentmethod for obstructive sleep apnea which avoids the use of surgery orcumbersome mechanical devices.

These and other objects are achieved in accordance with the presentinvention by providing a method of inhibiting sleep apnea in a mammalcomprising administering to said mammal an effective sleep apneainhibiting amount of6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred active form of6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide is(3R, 6R) -N- [(6-methyl-5-oxo-3-thiomorpholinyl)carbonyl]-L-histidyl-L-prolinamide tetrahydrate. For convenience, thissubstance will be referred to hereinafter by its international,non-proprietary name, Montirelin. Montirelin is a known compound whichexhibits central nervous system stimulating effects. It has beensuggested for possible use as an anti-depressant or in the treatment ofloss of consciousness caused by head concussion. The preparation of thiscompound is described e.g. in Schwertner et al., U.S. Pat. No.4,045,556, the disclosure of which is incorporated herein by reference.

Montirelin may be administered in various ways. For reasons of patientconvenience, orally administrable forms are desirable. It may also besuccessfully administered by intravenous injection of sterile solutions.Preferred dosages may range from about 0.05 mg/kg/day to about 50mg/kg/day. Dosages in the range from about 200 μg/kg/day to about 400μg/kg/day are particularly preferred. It is understood that the optimumdosage may vary depending on the patient and the severity of thecondition being treated, and it is considered within the skill of theart to optimize the dosage within the indicated range.

The active substance may be administered as such as a free base or inthe form of a salt with a pharmaceutically acceptable inorganic acid,such as hydrochloric acid, sulfuric acid or phosphoric acid, or organicacid such as acetic acid, benzoic acid, maleic acid, fumaric acid,tartaric acid, benzene sulfonic acid, etc.

The active substance may be formulated in the form of sterile solutionsor in tablets, capsules, dragees, syrups, granules, suppositories,sprays, etc. with various known pharmaceutical carriers or diluents suchas water, mineral oil, syrups, polyethylene glycol, lactose, cornstarch, paraffin and the like, and may be mixed with known adjuvantssuch as stabilizers, suspending agents, binders, viscosity improvers,flavors, coloring agents, preservatives, etc.

For purposes of illustration, useful dosage forms may be prepared asfollows:

Example Oral Tablet Formulation

Tablets may be prepared comprising the following ingredients in parts byweight:

    ______________________________________                                        Montirelin        10 parts                                                    lactose monohydrate                                                                             64 parts                                                    corn starch       20 parts                                                    polyvinylpyrrolidone                                                                             5 parts                                                    (Polyvidone K 30)                                                             magnesium stearate                                                                               1 part                                                     ______________________________________                                    

The active compound, lactose monohydrate and corn starch are sievedthrough a 0.63 mm sieve, mixed in a cube blender for 10 minutes,granulated with an aqueous solution of polyvinylpyrrolidone in water (50g in 200 ml of water), dried, sized through an 0.8 mm sieve togetherwith the magnesium stearate, mixed and pressed into tablets having adiameter of 6 mm and an average weight of 100 mg using a conventionaltablet press such as a Korsch EK 0 eccentric press.

Example Oral Liquid Formulation

An orally administrable liquid formulation may be prepared comprisingthe following ingredients in parts by weight:

    ______________________________________                                        Montirelin      10 parts                                                      potassium sorbate                                                                             10 parts                                                      sodium citrate   6 parts                                                      citric acid      2 parts                                                      sodium chloride  2 parts                                                      sucrose         200 parts                                                     ______________________________________                                    

sufficient water to make desired solution volume containing 10 gMontirelin per liter of solution. The solid ingredients were alldissolved in water, filtered through a 0.23 μm membrane and filled intobottles. 1 ml of the resulting solution contained 10 mg of Montirelin.Individual dosing can be achieved by administering individual volumes ofthe solution to the patient.

Example Nasal Spray Formulation

A nasal spray formulation may be prepared comprising the followingingredients in parts by weight:

    ______________________________________                                        Montirelin          80 parts                                                  benzalkonium chloride                                                                              1 part                                                   polyoxyethylene (20) sorbitan                                                                     80 parts                                                  monooleate (Polysorbate 80)                                                   sodium carboxymethylcellulose                                                                     80 parts                                                  (Tylose ™ C 30)                                                            disodium hydrogen phosphate                                                                       72 parts                                                  sodium dihydrogen phosphate                                                                       32 parts                                                  dextrose            240 parts                                                 ______________________________________                                    

purified water to make desired solution volume containing 10 gMontirelin per liter of solution.

The solid ingredients were all dissolved in the water, filtered througha 0.5 μm membrane and, filled into bottles topped by a spray pump with avolumetric dispensing chamber of 100 μl for nasal administration.

Toxicity

The subacute repeated-dose intravenous toxicity of Montirelin wasinvestigated in Sprague-Dawley rats treated repeatedly at 0.05, 0.5,5and 50 mg/kg/day for five weeks, and the reversibility of its toxiceffects was also investigated by a four-week recovery study.

Eight nine SPF Slc:SD rats of both sexes (age: four weeks, body weight:70.0-81.6 g) were purchased from Shizuoka Agriculture CooperativeAssociation for Laboratory Animals. During a one-weekquarantine/acclimation period, the animals were measured for body weightand observed for any general symptoms, and healthy animals showingnormal growth were selected and used in the experiment at the age offive weeks.

Males and females were used in five groups (including the control group)of 10 animals/sex, and additional 10 animals/sex were added to thecontrol, 0.5 mg/kg and 50 mg/kg groups to investigate the reversibilityof the toxic effect of the test substance. All these animals wererandomized to each group by weight stratification so that thedifferences in initial mean body weight were within 2% between groups.At the start of the treatment, the body weight was 116.5-132.9 g formales and 107.0-123.4 g for females.

The maximal dose was set at 50 mg.kg which is three lower doses were setat 5, 0.5 and 0.05 mg/kg using a common ratio of 1/10. This study alsoincluded the vehicle control group.

The experimental design (doses, number of animals/group andconcentrations of the dosing solution) is presented in Table I.

                  TABLE I                                                         ______________________________________                                        Subacute toxicity study of Montirelin in rats                                          Number of animals                                                             Administration period                                                                       Volume of Test                                                  (5 weeks)     Substance                                              Sex   Group    Recovery period (4 weeks)                                                                     (ml/Kg)                                                                             (W/V %)                                  ______________________________________                                        Male  Control* 20        10      5     0                                            0.0 mg/kg                                                                              10        --      5     0.001                                        0.5 mg/kg                                                                              20        10      5     0.01                                           5 mg/kg                                                                              10        --      5     0.1                                           50 mg/kg                                                                              20        10      5     1                                      Female                                                                              Control* 20        10      5     0                                            0.0 mg/kg                                                                              10        --      5     0.001                                        0.5 mg/kg                                                                              20        10      5     0.01                                           5 mg/kg                                                                              10        --      5     0.1                                           50 mg/kg                                                                              20        10      5     1                                      ______________________________________                                         *physiological saline                                                    

Dosing solutions were prepared by dissolving a weighed amount of thetest substance in physiological saline at a concentration of 1 W/V %using a volumetric flask. Lower dosing solutions were obtained bysuccessive 10-fold dilution of the initial solution. The respectivedosing solution was repeatedly administered intravenously once daily for35 days into the tail vein at a rate of 0.2 ml/10 sec. using a 1/4syringe for injection. The treatment was given at a constant volume of0.5 ml/100 g body weight in all dose groups, and the control group wastreated with physiological saline at the same volume in the same manner.

Clinical signs in all animals were observed daily between two and fourhours after dosing according to Irwin's method of comprehensiveobservational assessment, and the type, severity, onset time anddisappearance time of toxic symptoms were recorded. During the recoveryperiod, the clinical observation was performed once daily in the morningin the same manner. The body weight, food consumption and waterconsumption were measured in all animals three times weekly in themorning throughout the treatment and recovery periods and recorded.

Throughout the administration and recovery periods, no death occurred inany treatment or control groups.

1. In the 50 mg/kg group, systemic tremor was observed transientlyduring the injection in both sexes form day 0 (the initial dosing day),but this symptom gradually regressed from day 1 with increasing day oftreatment, disappearing by day 6 in males and by day 4 in females. Inthe 5 mg/kg or higher groups, almost all males and females showedtransient polyuria, and this effect peaked at about one hour afterdosing from day 0-3. However, this symptom also regressed as thetreatment day increased, disappearing by day 4-28. There were no otherremarkable clinical signs throughout the administration and recoveryperiods.

2. The water consumption increased in both sexes receiving 5 mg/kg orabove from day 2-3 until about week 4. Treated males tended to decreasefood consumption as compared with the control males, and, reflectingthis effect, the body weight gain was suppressed in males, particularlythose receiving 0.5, 5 and 50 mg/kg. In females, changes in foodconsumption and body weight were unremarkable.

3. The urinary findings were unremarkable except for an increase inurine volume in males receiving 5 mg/kg or above and females receiving 5mg/kg or above at week 2 and 5 of treatment.

4. Hematologically, both sexes receiving 50 mg/kg showed increasingtendency in red blood cell count, hemoglobin and hematocrit to increaseand decreasing tendency in total white blood cell count. However, allthese changes were within the range of normal physiological variations.Changes in other hematological parameters were not related to the dose.

5. No treatment-related abnormalities were observed in the bloodbiochemical parameters.

6. At autopsy, no treatment-related grossly abnormal changes ereobserved. Histopathologically, the incidence of hypertrophy of serouscells in the submaxillary gland showed dose-dependency in both sexes ofall treatment groups. In other organs, no remarkable changes were shownat the light microscopic level, nor were there any abnormal changes inthe liver or kidney at the electron microscopical examination.

All observed changes were reversed by discontinuing administration ofthe active compound.

EXAMPLE 1

The efficacy of Montirelin in treating obstructive sleep apnea wasdemonstrated in a standard English bulldog test model. Five bulldogswere implanted with subcutaneous electroencephalogram (EEG) electrodesand instrumented with respiratory oscillation belts (Respitrace™) tomeasure abdominal and ribcage movements and with an ear oximeter tomeasure oxygen saturation (SaO₂). Each dog was observed for an eighthour period, and waking and sleep behavior was noted. Montirelin in asterile saline vehicle was administered intravenously to the testanimals at a dosage of 100 μg/kg. Each test with active substance waspreceded by a control day in which only the saline vehicle wasadministered. The effect of Montirelin on hypersomnolence and sleepdisordered breathing was assessed.

Hypersomnolence was determined by sleep latency and total sleep time.Total sleep time (TST) is expressed as a percentage calculated bydividing the total sleep time in minutes by the total study time inminutes and multiplying the resulting quotient by 100 according to theformula: ##EQU1## The results are shown in the following Table II:

                  TABLE II                                                        ______________________________________                                                       TST (%)    TST (%)                                             Test Dog No.   Saline Control                                                                           Montirelin                                          ______________________________________                                        1              16.0       18.5                                                2              16.7       17.0                                                3              26.4       26.7                                                4              32.6       17.0                                                5              12.6        3.0                                                Average        20.9 ± 8.3                                                                            16.4 ± 8.5                                       ______________________________________                                    

Sleep latency was defined as the total minutes until the onset ofnon-REM sleep. The results observed during the test are shown in thefollowing Table III:

                  TABLE III                                                       ______________________________________                                        Test Dog   Sleep Latency (min)                                                                        Sleep Latency (min)                                   No.        Saline Control                                                                             Montirelin                                            ______________________________________                                        1          113           47                                                   2          79           149                                                   3          79           145                                                   4          93           150                                                   5          93           219                                                   Average    91.4 ± 14 142 ± 61.4                                         ______________________________________                                    

Sleep disordered breathing was evaluated in terms of a sleep disorderedbreathing index (SDBI) defined as the total number of rapid eye movement(REM) events divided by a quantity equal to the total REM time dividedby 60 minutes according to the formula: ##EQU2## A REM event (apnea) isdefined as an incident of decreased or absent respiration and a decreaseof 4% or more in the saturated blood oxygen (SaO₂) level occurringduring REM sleep. The results of the sleep disordered breathing test aretabulated in the following Table IV:

                  TABLE IV                                                        ______________________________________                                                       SDBI       SDBI                                                Test Dog No.   Saline Control                                                                           Montirelin                                          ______________________________________                                        1              4.4        7.2                                                 2              17.5       8.2                                                 3              15.5       2.6                                                 4              8.7        0.0                                                 5              33.2       25.7                                                Average        15.9 ± 11                                                                             8.7 ± 10                                         ______________________________________                                    

It can be seen that Montirelin produced an approximately 50% reductionin sleep disordered breathing associated with only a slight reduction intotal sleep time. Although sleep may be somewhat shallower, theMontirelin-treated test animals awaken less frequently and thus exhibitmarkedly better consolidated sleep patterns.

EXAMPLE 2

In a further experiment, Montirelin was administered on different daysat varying dosage levels to one bulldog with moderately severeobstructive sleep apnea. In this bulldog, a double-blind study wasconducted in which saline was administered as a control and fourdifferent doses of Montirelin (100 mg/kg, 200 mg/kg, 400 mg/kg and 800mg/kg) were administered. The dog was studied on four different days ateach dose of the active compound. On each day the dog was observed forsix hours following administration of the drug or control by i.v.injection. The order of different doses of drug or saline control wasrandomized, and a wash-out period of two days was allowed after study ofa particular dose. During the studies, respiratory movement, oxygensaturation and electroencephalogram for sleep state were measured. Thenumber of sleep-disordered breathing events or respiratory disturbanceincidents (RDI) per hour was calculated according to the formula givenabove both for non-rapid eye movement (non-REM) sleep, which occupiesthe majority of sleep time, and rapid eye movement (REM) sleep. Meansleep efficiency and arousal index were also determined. The results areshown in the following Table V:

                  TABLE V                                                         ______________________________________                                        Montirelin                                                                            Saline   100      200    400    800                                   Level   Control  mg/kg    mg/kg  mg/kg  mg/kg                                 ______________________________________                                        Mean Sleep                                                                             39%      41%      37%    40%    38%                                  Efficiency                                                                    Arousal 12       16        7     12      6*                                   Index                                                                         non-REM  6        8        0*     4      2*                                   Sleep RDI                                                                     REM Sleep                                                                             44       53       70     N/A    N/A                                   RDI                                                                           Lowest O.sub.2                                                                        89       92       86     92     93                                    Saturation                                                                    ______________________________________                                         *p < 0.05                                                                

The data show that there is a significant reduction in non-REMsleep-disordered breathing events at drug levels of 200 mg/kg and above.In this test animal, there does not appear to have been an impact on REMsleep RDI at lower dose levels. At higher dosages of 400 mg/kg and 800mg/kg, the animal did not enter REM sleep, so that the number of REMsleep breathing episodes could not be studied at these dose levels. Theactive compound did not affect sleep efficiency, but did reduce thenumber of arousals per hour. There was no effect on oxyhemoglobinsaturation during breathing episodes. These results show that Montirelinproduces a dose-dependent reduction in the number of episodes wherebreathing declines during non-REM sleep, and thereby indicate thatMontirelin administration may be considered to show promise as atreatment for alleviating non-REM sleep disordered breathing.

In practice, Montirelin may be administered as a bolus from 0 to 12hours, preferably from 0.2 to 6 hours, prior to a normal sleepingperiod. The active compound may be administered orally or parenterally,e.g. by intramuscular injection, subcutaneous injection, intranasalinhalation, rectal administration or intravenous administration.

Without being bound to any theory, it is believed that Montirelin actsby potentiating the activity of motoneurons controlling the musculatureof the airway during sleep, thereby preventing the loss of muscle toneassociated with obstructive events.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed to include everything within the scope ofthe appended claims and equivalents thereof.

What is claimed is:
 1. A method of inhibiting sleep apnea in a mammalcomprising administering to said mammal an effective sleep apneainhibiting amount of6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide isadministered by intravenous injection of a sterile isotonic salinesolution thereof.
 3. A method according to claim 1, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide isadministered at a dosage of from about 0.05 mg/kg/day to about 50mg/kg/day.
 4. A method according to claim 3, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide isadministered at a dosage in the range from about 200 μg/kg/day to about400 μg/kg/day.
 5. A method according to claim 3, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide isadministered at a dosage of about 100 μg/kg/day.
 6. A method accordingto claim 1, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered as a bolus from0 to 12 hours prior to a normal sleeping period.
 7. A method accordingto claim 1, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered orally.
 8. Amethod according to claim 1, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered parenterally.9. A method according to claim 8, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered byintramuscular injection.
 10. A method according to claim 8, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered by intranasalinhalation.
 11. A method according to claim 8, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered intravenously.12. A method according to claim 8, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered subcutaneously.13. A method according to claim 8, wherein6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide or apharmaceutically acceptable salt thereof is administered rectally.